Skip to main content
Log in

Interspecies Pharmacokinetic Modeling of Subcutaneous Absorption of Rituximab in Mice and Rats

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

To investigate the effect of dose level and anatomical site of injection on the pharmacokinetics of rituximab in mice, and to evaluate the utility of a pharmacokinetic model for describing interspecies differences in subcutaneous absorption between mice and rats.

Methods

Rituximab serum concentrations were measured following intravenous and subcutaneous administration at the back and abdomen of mice. Several approaches were compared for scaling model parameters from estimated values in rats.

Results

The bioavailability of rituximab following subcutaneous injection was inversely related to the dose level and was dependent on the site of injection in mice. The overall rate of absorption was faster in mice as compared to rats. Subcutaneous absorption profiles were well described using the proposed structural model, in which the total receptor concentration, the affinity of rituximab to the receptor, and the degradation rate constant were assumed to be species independent.

Conclusions

Subcutaneous absorption processes show similar trends in rats and mice, although the magnitude differs between species. A mathematical model that combines the absorption of free and bound antibody with presystemic degradation successfully captured rituximab pharmacokinetics in both species, and approaches for sharing and scaling parameters between species were identified.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

FcRn:

Neonatal Fc receptor

IV:

Intravenous

mAbs:

Monoclonal antibodies

SC:

Subcutaneous

References

  1. Richter WF, Bhansali SG, Morris ME. Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J. 2012;14(3):559–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Bittner B, Schmidt J. Subcutaneous administration of monoclonal antibodies in oncology as alternative to established intravenous infusion. Pharm Ind. 2012;74(4):638–43.

    CAS  Google Scholar 

  3. Aue G, Lindorfer MA, Beum PV, Pawluczkowycz AW, Vire B, Hughes T, et al. Fractionated subcutaneous rituximab is well-tolerated and preserves CD20 expression on tumor cells in patients with chronic lymphocytic leukemia. Haematologica. 2010;95(2):329–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Swartz MA. The physiology of the lymphatic system. Adv Drug Deliv Rev. 2001;50(1–2):3–20.

    Article  CAS  PubMed  Google Scholar 

  5. Porter CJ, Charman SA. Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci. 2000;89(3):297–310.

    Article  CAS  PubMed  Google Scholar 

  6. Kagan L, Gershkovich P, Mendelman A, Amsili S, Ezov N, Hoffman A. The role of the lymphatic system in subcutaneous absorption of macromolecules in the rat model. Eur J Pharm Biopharm. 2007;67(3):759–65.

    Article  CAS  PubMed  Google Scholar 

  7. McDonald TA, Zepeda ML, Tomlinson MJ, Bee WH, Ivens IA. Subcutaneous administration of biotherapeutics: current experience in animal models. Curr Opin Mol Ther. 2010;12(4):461–70.

    CAS  PubMed  Google Scholar 

  8. Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S. Projecting human pharmacokinetics of therapeutic antibodies from nonclinical data: What have we learned? MAbs. 2011;3(1):61–6.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Chen T, Mager DE, Kagan L. Interspecies modeling and prediction of human exenatide pharmacokinetics. Pharm Res. 2013;30(3):751–60.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Woo S, Jusko WJ. Interspecies comparisons of pharmacokinetics and pharmacodynamics of recombinant human erythropoietin. Drug Metab Dispos. 2007;35(9):1672–8.

    Article  CAS  PubMed  Google Scholar 

  11. Kagan L, Abraham AK, Harrold JM, Mager DE. Interspecies scaling of receptor-mediated pharmacokinetics and pharmacodynamics of type I interferons. Pharm Res. 2010;27(5):920–32.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Kagan L, Turner MR, Balu-Iyer SV, Mager DE. Subcutaneous absorption of monoclonal antibodies: role of dose, site of injection, and injection volume on rituximab pharmacokinetics in rats. Pharm Res. 2012;29(2):490–9.

    Article  CAS  PubMed  Google Scholar 

  13. Kagan L, Mager DE. Mechanisms of subcutaneous absorption of rituximab in rats. Drug Metab Dispos. 2013;41(1):248–55.

    Article  CAS  PubMed  Google Scholar 

  14. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58.

    Article  CAS  PubMed  Google Scholar 

  15. Deng R, Meng YG, Hoyte K, Lutman J, Lu Y, Iyer S, et al. Subcutaneous bioavailability of therapeutic antibodies as a function of FcRn binding affinity in mice. MAbs. 2012;4(1):101–9.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Kota J, Machavaram KK, McLennan DN, Edwards GA, Porter CJ, Charman SA. Lymphatic absorption of subcutaneously administered proteins: influence of different injection sites on the absorption of darbepoetin alfa using a sheep model. Drug Metab Dispos. 2007;35(12):2211–7.

    Article  CAS  PubMed  Google Scholar 

  17. Beshyah SA, Anyaoku V, Niththyananthan R, Sharp P, Johnston DG. The effect of subcutaneous injection site on absorption of human growth hormone: abdomen versus thigh. Clin Endocrinol (Oxford). 1991;35(5):409–12.

    Article  CAS  Google Scholar 

  18. Macdougall IC, Jones JM, Robinson MI, Miles JB, Coles GA, Williams JD. Subcutaneous erythropoietin therapy: comparison of three different sites of injection. Contrib Nephrol. 1991;88:152–6. discussion 7–8.

    CAS  PubMed  Google Scholar 

  19. Kagan L, Gershkovich P, Wasan KM, Mager DE. Dual physiologically based pharmacokinetic model of liposomal and nonliposomal amphotericin B disposition. Pharm Res. 2014;31(1):35–45.

    Article  CAS  PubMed  Google Scholar 

  20. Mager DE. Target-mediated drug disposition and dynamics. Biochem Pharmacol. 2006;72(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  21. Hansen RJ, Balthasar JP. Pharmacokinetic/pharmacodynamic modeling of the effects of intravenous immunoglobulin on the disposition of antiplatelet antibodies in a rat model of immune thrombocytopenia. J Pharm Sci. 2003;92(6):1206–15.

    Article  CAS  PubMed  Google Scholar 

  22. Dong JQ, Salinger DH, Endres CJ, Gibbs JP, Hsu CP, Stouch BJ, et al. Quantitative prediction of human pharmacokinetics for monoclonal antibodies: retrospective analysis of monkey as a single species for first-in-human prediction. Clin Pharmacokinet. 2011;50(2):131–42.

    Article  CAS  PubMed  Google Scholar 

  23. Wang W, Prueksaritanont T. Prediction of human clearance of therapeutic proteins: simple allometric scaling method revisited. Biopharm Drug Dispos. 2010;31(4):253–63.

    PubMed  Google Scholar 

  24. Jolling K, Perez Ruixo JJ, Hemeryck A, Vermeulen A, Greway T. Mixed-effects modelling of the interspecies pharmacokinetic scaling of pegylated human erythropoietin. Eur J Pharm Sci. 2005;24(5):465–75.

    Article  CAS  PubMed  Google Scholar 

  25. Mager DE, Neuteboom B, Efthymiopoulos C, Munafo A, Jusko WJ. Receptor-mediated pharmacokinetics and pharmacodynamics of interferon-beta1a in monkeys. J Pharmacol Exp Ther. 2003;306(1):262–70.

    Article  CAS  PubMed  Google Scholar 

  26. Gao W, Jusko WJ. Target-mediated pharmacokinetic and pharmacodynamic model of exendin-4 in rats, monkeys, and humans. Drug Metab Dispos. 2012;40(5):990–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Rath T, Kuo TT, Baker K, Qiao SW, Kobayashi K, Yoshida M, et al. The immunologic functions of the neonatal Fc receptor for IgG. J Clin Immunol. 2013;33 Suppl 1:S9–17.

    Article  PubMed  Google Scholar 

  28. Salar A, Bouabdallah R, McIntyre C, Sayyed P, Bittner B. A two-stage phase Ib stufy to investigate the pharmacokinetics, safety and tolerability of subcutaneous rituximab in patients with follicular lymphoma as part of maintenance treatment. 53rd American Society of Hematology Annual Meeting and Exposition; December 10–13, 2011; San Diego, CA, 2010.

  29. Assouline S, Buccheri V, Delmer A, Doelken G, Gaidano G, McIntyre C, et al. Subcutaneous rituximab in combination with fludarabine and cyclophosphamide for patients with CLL: initial results of a phase Ib study (SAWYER [BO25341]) show non-inferior pharmacokinetics and comparable safety to that of intravenous rituximab. 54th American Society of Hematology Annual Meeting and Exposition; December 8–11, 2012; Atlanta, GA, 2012.

Download references

ACKNOWLEDGMENTS AND DISCLOSURES

This work was supported, in part, by the Center for Protein Therapeutics, University at Buffalo, State University of New York.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Leonid Kagan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kagan, L., Zhao, J. & Mager, D.E. Interspecies Pharmacokinetic Modeling of Subcutaneous Absorption of Rituximab in Mice and Rats. Pharm Res 31, 3265–3273 (2014). https://doi.org/10.1007/s11095-014-1416-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-014-1416-1

KEY WORDS

Navigation